Abstract

Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST. Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.

Histological examination of the NAc after gene transfer. A, Expression of CREB 5 d after microinjection of HSV-CREB into the left NAc shell (40× magnification). The arrow indicates the injection site. Scale bar, 1 mm. B, Higher magnification (200×) of the injection site in A, confirming nuclear localization of CREB expression. Expression of mCREB (data not shown) is indistinguishable from that of CREB. C, An adjacent, Nissl-stained slice from the same brain. AC, Anterior commissure. The arrow indicates the injection site.

Effect of HSV treatments on the FST. A, Latencies to become immobile depended on viral vector treatment when transgene expression was maximal (days 3 and 4). Latencies were decreased in rats treated with HSV-CREB and increased in rats given HSV-mCREB. HSV-LacZ had no effect. Data are expressed as latencies (mean ± SEM, in seconds) during the 5 min test on day 4. There were no group differences when activity rather than swimming was quantified during testing ( B) or when the FST was conducted after transgene expression had diminished ( C) (days 10 and 11). Data in C are expressed as latencies during the 5 min test on day 11. D, Gene transfer did not affect rat weights, but rats tested on day 11 weighed more than rats tested on day 4. **p < 0.01 compared with sham-treated rats; Fisher’s t test.

A, Effect of norBNI (5.0 or 20 μg, i.c.v.) on the FST. Treatment with norBNI dose-dependently increased latencies to become immobile (mean ± SEM) in each group. *p < 0.05, **p < 0.01 (Fisher’s t tests), compared with no intracerebroventricular for each treatment. B, There were no effects of norBNI (20 μg, i.c.v.) when locomotor activity rather than swimming was quantified during testing.

A, Locations from which NAc shell and CPU tissue punches were obtained (). B, Western immunoblot of P-CREB in the NAc shell and CPU after 15 min of forced swimming (Sw). Control rats did not undergo swimming (No Sw). Forced swimming significantly increased P-CREB expression in the NAc but had no effect in the CPU. Data are expressed as the ratio (mean ± SEM; 6 rats per group) of P-CREB expression in the Sw and No Sw groups for each region. *p < 0.05; Student’s t test.